Perinatal asphyxia is a serious complication of childbirth, which affects about 1% of newborns world-wide. It may lead to hypoxia-ischemia or more generally to injury to the baby due to lack of (sufficient) oxygen.
In particular at risk of such damage is the brain. For instance, hypoxia-ischemia during childbirth may result in neonatal encephalopathy, cerebral palsy, mental retardation, learning disabilities, epilepsy or other long-term effects. For a large part, these effects are caused by excessive formation of free radicals such as superoxide and hydroxyl radicals. These radicals are especially formed directly after a period of hypoxia-ischemia when reoxygenation and reperfusion are re-established. Together with NO (nitric oxide) superoxide reacts to peroxynitrite, which attacks the brain cell membranes, resulting in lipid peroxidation and eventually cell death.
It has been suggested in the art to prevent or treat the above effects by administering, to neonates that are at risk, free radical scavengers and/or xanthine oxidase inhibitors such as allopurinol (“ALLO”) or non-protein bound iron chelators such as deferoxamine (“DFO”). In a pilot study in newborn babies and in experimental studies it has been shown that allopurinol and deferoxamine reduce free radical-induced brain damage in newborns to some extend, these compounds, however, are still not fully satisfactory.
Since excessive biosynthesis of NO results in perinatal destruction of neurons, the use of nitric oxide synthase inhibitors seems to be promising in reducing brain injury after perinatal hypoxia-ischemia. However, data concerning non-specific NOS inhibitors after hypoxia-ischemia are conflicting: for instance it has been shown that NG-nitro-L-arginine (NNLA) compromised cerebral energy status during and after hypoxia-ischemia (HI) in newborn piglets (Groenendaal et al, Pediatric Res. 45 (1999) 827–833), whereas L-nitro-arginine methyl ester (L-NAME) was neuroprotective in neonatal rats (Palmer et al., Pediatric Res. 41 (1997) 294A). Nowadays, three types of NOS isoforms have been characterised: neuronal, inducible and endothelial NOS. Using selective NOS inhibitors and transgenic animals it has been suggested that the NOS isoform determines whether it acts neuroprotective or neurotoxic upon HI (Bolaños and Almeida, Biochim. Biophys. Acta 1411 (1999), 415–436). Johnston et al (Semin. Neonatal. 2000(5): 75–86) showed that 7-nitroindazole, mainly a neuronal NOS inhibitor but only injectable intraperitoneally, was effective in reducing apoptosis and reducing the levels of citrulline. Higuchi et al (Eur. J. Pharmacology 342 (1998) 47–49) and Tsuji et al (Pediatric Res. 47 (2000), 79–83) reported that aminoguanidine, mainly an inducible NOS inhibitor, reduced infarct volumes in neonatal rats. On the other hand, endothelial NOS knock-out mice were highly sensitive to cerebral ischemia, suggesting a role for eNOS in cerebral perfusion. NOS inhibitors with potential usefulness in reducing brain injury after perinatal HI need to be water-soluble for rapid intravenous injection in mother or newborn child/animal and need to be transported to the brain and be selective inhibitive for neuronal and inducible NOS.
Until now no accepted therapy is available for asphyxiated infants. Therefore, there is a need for pharmaceutical preparations that may be used to prevent and/or treat, in newborn babies, the effects of complications that may occur during childbirth.
In addition, as already mentioned above, there is also a need for veterinary preparations that can be used for the same or similar purposes is newborn animals or to improve growth after birth. Also, there is a need for pharmaceutical preparations that can be used to prevent and/or treat (the effects of) brain cell injury in people of all ages.